cefiderocol

Overview

Cefiderocol is a siderophore cephalosporin antibiotic used in the treatment of serious Gram-negative bacterial infections. Its defining pharmacologic feature is iron transport–mediated entry into bacterial cells: the molecule is designed to exploit bacterial iron uptake systems, which can enhance penetration into organisms that are otherwise difficult to treat because of permeability barriers and multidrug resistance. This mechanism has made cefiderocol of particular interest for pathogens with complex resistance profiles, including carbapenem-resistant Enterobacterales and non-fermenting Gram-negative bacilli.

Clinically, cefiderocol is positioned as a therapy for infections caused by highly resistant organisms when conventional options are limited. Recent research has focused on its activity against pathogens such as Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales, as well as on resistance mechanisms that may reduce susceptibility, including β-lactamase variants and other adaptive changes in resistant bacteria.

Focus of Latest Publications

Recent publications have examined cefiderocol primarily as a treatment option for difficult-to-treat Gram-negative infections and as a probe for understanding resistance biology.

A multicenter real-world study and literature review evaluated cefiderocol for Stenotrophomonas maltophilia infections in adult patients treated across three tertiary-care hospitals between 2021 and 2024. The authors noted that cefiderocol has shown potent in vitro activity against S. maltophilia, while also emphasizing that clinical evidence remains limited. Their findings were interpreted as supporting cefiderocol as an effective and well-tolerated option, especially when conventional therapies are constrained.

Another real-world study focused on hematologic patients with malignancies, aiming to characterize cefiderocol use and outcomes in this vulnerable population. This work reflects ongoing interest in cefiderocol for immunocompromised hosts, where resistant Gram-negative infections can be particularly consequential and therapeutic choices are often restricted.

Several studies investigated cefiderocol in the context of antimicrobial resistance mechanisms. One analysis of carbapenem-resistant Acinetobacter baumannii isolates reported that a Val292 substitution combined with an alanine duplication in the Ω loop of ADC β-lactamase can confer reduced susceptibility to advanced β-lactam agents, including cefiderocol. This underscores that cefiderocol activity can be compromised by specific β-lactamase structural changes.

Work on the KPC family of β-lactamases also implicated cefiderocol in substrate specificity studies. Variants at Ambler position 104 showed enhanced hydrolysis of ceftazidime and cefiderocol, indicating that certain KPC mutations may broaden enzymatic activity against newer β-lactams.

In Pseudomonas aeruginosa, resistance evolution under ceftazidime-avibactam exposure was studied with attention to cross-resistance patterns across newer agents. Cross-resistance was common between ceftazidime-avibactam and ceftolozane-tazobactam, less common for imipenem-relebactam and cefepime-zidebactam, and lowest for cefiderocol. This suggests cefiderocol may retain activity in some resistance backgrounds where other novel β-lactams are compromised.

Additional in vitro surveillance studies assessed cefiderocol against metallo-β-lactamase-producing Enterobacterales. In France, cefiderocol showed reduced overall activity, with susceptibility reported at 74.9%, and reduced efficacy was mainly observed among NDM-producing isolates. In India, a study highlighted the outstanding presence of New Delhi metallo-β-lactamase in carbapenem-resistant Enterobacterales while emphasizing the exceptionally potent in vitro activity of cefiderocol and aztreonam-avibactam, supporting the need for immediate access to these agents in that setting.

Taken together, these studies position cefiderocol as an important option against highly resistant Gram-negative pathogens, while also showing that its activity can be affected by specific β-lactamases and resistance evolution. The literature also places cefiderocol in comparative context with aztreonam-avibactam, ceftazidime-avibactam, amoxicillin, and polymyxins, reflecting broader efforts to define where this agent fits among available therapies for multidrug-resistant infections.

Key Publications

Jun Cefiderocol for Stenotrophomonas maltophilia infections: real-world evidence from a multicenter study and a comprehensive literature review. (Journal of chemotherapy (Florence, Italy), 2026, PMID 42283423): "These findings support cefiderocol as an effective and well-tolerated option for S. maltophilia infections, particularly when conventional therapies are limited."
Jun Real-World Experience with Cefiderocol in Hematologic Patients with Malignancies. (International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2026, PMID 42264071): "we aimed to characterize cefiderocol use and outcomes in haematological patients."
May A Val292 substitution combined with an alanine duplication (ADUP) in the Ω loop of ADC β-lactamase confers reduced susceptibility to advanced β-lactam agents, including cefiderocol. (mBio, 2026, PMID 41949313): "Given the increasing clinical use of these agents, including cefiderocol, we analyzed the diversity and function of ADC variants in a global collection of carbapenem-resistant A. baumannii (CRAb) isolates."
May Ceftazidime-avibactam resistance evolution in Pseudomonas aeruginosa and implications for cross-resistance to other novel β-lactams. (Antimicrobial agents and chemotherapy, 2026, PMID 41940815): "Cross-resistance was common between ceftazidime-avibactam and ceftolozane-tazobactam, less common for imipenem-relebactam and cefepime-zidebactam, and lowest for cefiderocol."
May Comparative in vitro efficacy of aztreonam-avibactam and other alternatives (cefepime-taniborbactam, cefepime-zidebactam, and cefiderocol) against metallo-β-lactamase-producing Enterobacterales isolated in 2024 in France. (Antimicrobial agents and chemotherapy, 2026, PMID 41891866): "Cefepime-taniborbactam and cefiderocol showed reduced overall activity (76.4% and 74.9% susceptibility, respectively), with reduced efficacy mainly observed among NDM-producing isolates."
May Outstanding presence of New Delhi metallo-beta-lactamase in carbapenem-resistant Enterobacterales and exceptionally potent in vitro activity of cefiderocol and aztreonam-avibactam emphasises their immediate access in India. (Transactions of the Royal Society of Tropical Medicine and Hygiene, 2026, PMID 41869915): "Outstanding presence of New Delhi metallo-beta-lactamase in carbapenem-resistant Enterobacterales and exceptionally potent in vitro activity of cefiderocol and aztreonam-avibactam emphasises their immediate access in India."
May Role of Ambler Position 104 in Defining Substrate Specificity in the KPC Family of β-Lactamases. (ACS infectious diseases, 2026, PMID 42047351): "Steady-state kinetics confirmed enhanced hydrolysis of ceftazidime and cefiderocol by these variants."